1. Field of the Invention
This invention pertains to a process for preparing diacetylenics, to diacetylenic compounds and to reduced diacetylenic compounds.
2. Description of Related Art
Diacetylenic acids are a major precursor for making diacetylenic phospholipids, which are basic building materials for making and stabilizing technologically useful structures called xe2x80x9ctubulesxe2x80x9d. The high cost of the diacetylenic acids pushes the cost of phospholipids up thus making them less attractive in the development of technologies such as electronic devices; controlled release of substances, particularly drugs; drug delivery systems; nano composites; and the like. Diacetylenic phospholipids consisting of diacetylenic acids with keto functional groups, and a combination of keto and aryl or cyclic groups, constitutes useful molecular probes for studying bilayer membrane structures and dynamics.
The prior art process of making the isomeric diacetylenic acids, disclosed in U.S. Pat. No. 4,867,917, involves a heterocoupling reaction between a starting acetylenic acid and an omega haloalkyne. While the synthetic scheme provides an easy way to prepare any combination of diacetylenic acids, the cost of the starting diacetylenic acid is high enough to prevent commercial use of the product diacetylenic acids.
The patented prior art preparation of the diacetylenic acids noted above, is further complicated by the fact that it is disadvantageous from commercial as well as product purity points of view. Preparation of the haloalkyne requires three steps, starting with an alkene, such as dodecene, progressing to an alkyne by the use of bromine and a basic ethanol, and finally arriving at the haloalkyne with the aid of the Grignard reagent and iodine. Similarly, it takes two steps to prepare an alkanoic acid, such as dodecanoic acid, starting either with an alkylenic acid, such as dodecylenic acid, or from a reaction of lithium acetylide/ethylene diamine complex with a bromoalkenoic acid, such as 9-bromododecanoic acid.
The overall yields for making a haloalkyne and an acetylenic acid are in the range of 60% and the reactions involve expensive and air sensitive reagents. Moreover, coupling a haloalkyne and an acetylenic acid is not only a low yield reaction of about 25% but also provides a mixture of three products. Though the separation of individual products is easy, additional reaction steps add to the product cost. The cost of the diacetylenics of interest herein is on the order $4,000/kg when prepared by the prior art process. There is a clear need for a new procedure which should be more cost effective and which minimizes the use of hazardous chemicals.
It is an object of this invention to prepare diacetylenics using a procedure that is more cost-effective and which minimizes the use of hazardous chemicals.
Another object of this invention is new compounds of diacetylenics containing at least one keto group.
Another object of this invention is new diacetylenic compounds containing at least one saturated or unsaturated cyclic group.
Another object of this invention is the preparation of diacetylenics which contain adjoining acetylene groups and carbon chains of varying length on either side thereof.
Another object of this invention is the ability to vary chain length on the sides of the adjoining acetylene groups in the diacetylenics described herein.
These and other objects of this invention are accomplished by oxidative coupling reaction involving an acetylenic acid to produce a diacetylenic diacid which is subsequently converted to a novel diacetylenic keto compound, which in turn is reduced to a reduced diacetylenic compound.
This invention pertains to a high yield synthesis process, to diacetylenic compounds and to reduced diacetylenic compounds. More specifically, this invention pertains to a coupling process for making diacetylenics starting with an omega monoacetylenic acid, to diacetylenic compounds containing two adjacent acetylenic groups and to reduced diacetylenic compounds containing an alkyl or cyclic group at one or both ends thereof.
The versatile general procedure for making unsymmetric diacetylenics includes the steps of coupling an acetylenic acid using oxidative coupling involving cuprous chloride (CuCl), ethylamine (EtNH2) and hydroxylamine hydrochloride (NH2 OH.HCl) to form a diacetylenic diacid followed by reaction of one of the carboxyl moieties on the diacetylenic diacid with a lithium reagent RLi wherein R is alkyl, phenyl or the like group to generate a keto derivative to form the diacetylenic keto acid. In the next reaction step, the keto group at one end of the diacetylenic keto acid is reduced using either hydrogenation with Raney nickel W-7 as catalyst or alkaline hydrazine hydrate or triethylsilane/trifluoroacetic acid reagent or some other keto reducing agent. The general procedure can be illustrated as follows: 
where m is 1-35, more typically 2-8 carbon atoms; and R is selected from alkyl groups of 1-10, more typically 1-6 carbon atoms, and cyclic groups containing 3-35 carbon atoms, more typically aromatic monocyclic and multicyclic groups containing 6-15 carbon atoms; and X is a halogen, typically chloride.
In the general procedure given above, if the acetylenic acid is solid, it is dissolved in water and then converted to a salt, typically a sodium or potassium salt. The acetylenic acid is then coupled to itself in the presence of cuprous chloride catalyst, which is unstable and facilitates the coupling reaction. In place of cuprous chloride, one can use pyridine, tetramethylethylene diamine, an aliphatic amine of 1-6 carbon atoms or another suitable catalyst. The coupling reaction is also carried out in the presence of basic ethylamine (EtNH2), which dissolves and solubilizes cuprous chloride, and hydroxylamine hydrochloride (NH2 OH.HCl), which reduces any cupric chloride present as a result of conversion of cuprous chloride to cupric chloride (Cu++xe2x86x92Cu+). The coupling reaction is typically carried out at room temperature although it can be accelerated at elevated temperatures. Elevated temperatures that degrade reactants or products should be avoided. The coupling reaction can be carried out at 0-40xc2x0 C. and its duration is typically a minimum of about 2 hours and its termination can be confirmed by thin liquid chromatography (TLC). The coupling reaction is the first step in the process and its product is a symmetric diacetylenic dicarboxylic acid. Conversion of the coupling reaction is about 85%.
When cuprous chloride in ethylamine is added to the salt of the acetylenic acid, the reaction medium turns dark blue and several drops of hydroxylamine hydrochloride are added to the reaction medium to turn it light yellow temporarily since the reaction medium again turns dark blue. Addition of hydroxylamine hydrochloride is thus continued until the reaction medium remains yellow, indicating endpoint of the reaction step. Thin layer chromatography is typically used to confirm conversion of all acetylenic acid to the diacetylenic dicarboxylic acid.
In the next or the second step of the reaction, one or both of the carboxyl groups on the diacetylenic diacid are converted to a ketone by the lithium compound RLi where the R group is selected from alkyl and cyclic groups. The alkyl groups contain at least 1 carbon atom and typically up to about 6 carbon atoms whereas the aromatic groups are at least monocyclic containing at least 3 carbon atoms. The cyclic group can be a multicyclic, saturated or unsaturated group and can contain up to about 35, more typically up to about 14 carbon atoms. Typical alkyl groups suitable herein include methyl, ethyl, propyl, butyl and pentyl whereas typical aromatic groups contemplated herein include phenyl, naphthyl and biphenyl.
The lithium compound reacts with the two carboxylic groups and converts them to a first lithium salt in the following manner: 
the carbonyl oxygen of which is next converted to a second lithium salt as follows: 
Reaction medium is cloudy when formation of the first lithium salt takes place and becomes pinkish when formation of the second lithium salt takes place.
The lithium compound, in ether or hexane or tetrahydrofuran or another suitable aprotic solvent, is added to the diacetylenic diacid and converts one or both carboxylic acid groups to mono or dilithium carboxylate, as demonstrated above. Subsequent reaction of lithium compound takes place on the oxygen in keto group, and the inorganic acid then hydrolyzes the second lithium salt to a keto group in the following manner: 
General procedure for making 2-keto-omega carboxylic acid is as follows: Dissolve 1.0 mmol diacetylenic dicarboxylic acid in 10 ml dry tetrahydrofuran. Purge the reaction flask with nitrogen and let the slow stream of nitrogen flow through the reaction medium. To the stirred solution, 3.3 mol equivalent of lithium reagent is added with the aid of syringe. Usually it takes 2 mol equivalents to react with two dicarboxylic acid and 1.3 mol equivalents lithium to react with each carbonyl group. At first, a white precipitate of lithium salt of carboxylic acid is produced at first. Further addition produces colored lithium alkoxy salt. After the reaction is considered over, usually in 2-3 hours, the excess of lithium reagent is quenched by addition of 3 mol equivalents of trimethylsilyl chloride. The reaction is then stirred for additional 30 minutes before quenching it with 10% sulfuric acid. The upper organic layer thus produced is separated by addition of additional diethyl ether. The combined ethereal extract is washed twice with distilled water. The ether extract is dried over anhydrous magnesium sulfate. Removal of the solvent provides crude product. The pure compound can be isolated by crystallization as well as by column chromatography over silica gel. To react carbonyl groups from both carboxylic acid groups, a 6 mol equivalent of lithium compound is used.
The acid hydrolysis is achieved with sufficient inorganic acid to make the reaction acidic. Although any inorganic acid can be used, hydrochloric or sulfuric acids have been found to be practical. Prior to acid addition, a small amount on the order of 1 mol equivalent to RLi of trimethylsilyl chloride (TMSC) is added to avoid a side hydrolysis reaction. Without trimethylsilyl chloride, typically get some alcohol whereas with it, the hydrolysis reaction is avoided and all of the carboxyl groups are converted to the keto group(s).
It should be apparent that the reaction with the lithium compound RLi can result in preparation of symmetrical and unsymmetrical diacetylenic compounds depending on how many carbons there are in the R group, what type of group the R group is, and whether one or both sides of the diacetylenic compound is provided with the keto group. This scheme represents that starting from an acetylene acid with xe2x80x9cmxe2x80x9d methylene units within its hydrocarbon chain, a diacetylenic acid can be produced in which the number of methylene units xe2x80x9cnxe2x80x9d in the methyl ending segment are always mxe2x89xa71. Thus, starting with undecynoic acid with m=8, by reacting one end of a diacetylenic diacid with methyl lithium, ethyl lithium, propyl lithium, butyl lithium or pentyl lithium and then reducing the compound, one can produce acids with m=8 and n=9, 10, 11, 12 and 13 carbon atoms, as illustrated below:
COOHxe2x80x94(CH2)mxe2x80x94Cxe2x89xa1Cxe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)nxe2x80x94R
The second step of the reaction takes more than about 3 hours and up to about 5 hours, with the reaction phase with a lithium compound taking 3 or more hours, and the reaction phases with trimethylsilyl chloride and the inorganic acid taking a few minutes each. The endpoint of the second step of the process is typically determined with thin layer chromatography. Observation of a constant amount of the reactant or the product on thin layer chromatography plates indicates the completion of the reaction.
The diacetylenic keto compounds, i.e., the mono-keto and the di-keto diacetylenic compounds, also referred to herein as diacetylenic compounds, are novel and new compounds which can be used to make macrocyclics useful as pharmaceutical compounds.
The third step in the reaction is reduction of the keto group(s) in the manner shown: 
The reduction can be accomplished with Raney nickel, hydrazine hydrate/KOH reagent, or in any other suitable manner although the Raney nickel W-7 catalyst is typically used with an excess over the stoichiometric amount.
Synthesis of W-7 Raney nickel is well known. However, preparation of the catalyst is crucial for the reaction to proceed. The following method can be used in the preparation of catalyst. The W-7 Raney nickel reduction catalyst used herein was prepared by placing 600 ml of distilled water and 160 grams of sodium hydroxide pellets into a 2xe2x80x94liter Erlenmeyer flask equipped with a thermometer and a stirrer. The solution was stirred rapidly and allowed to cool to 50xc2x0 C. in an ice bath. Then, 125 g of Raney nickel-aluminum alloy powder was added in small portions during a period of 25-30 minutes. The temperature was maintained at 50∓2xc2x0 C. by controlling the rate of addition of alloy to the sodium hydroxide solution and the addition of the ice to the cooling bath. When all of the alloy has been added, the suspension was digested at 50∓2xc2x0 C. for 50 minutes with gentle stirring. It was necessary to remove the ice bath and replace it with a hot-water bath to keep the temperature constant. After this period of digestion, the catalyst was washed with three 1-liter portions of distilled water by decantation. Catalyst was transferred to a 250xe2x80x94ml centrifuge tube or bottle with 95% ethanol, with centrifuging after each addition. In the same manner, the catalyst was washed three times with absolute ethanol and was stored in a refrigerator in a closed bottle filled with absolute ethanol.
If both ends of the diacetylenic keto compounds contain the carboxyl oxygen of a keto group, then amount of the Raney nickel catalyst will be about twice as much if only one end of the compounds contained the group. If the compound is diacetylenic keto acid, i.e., a compound containing a carbonyl oxygen in a keto group at only one end whereas there is a carboxy group at the other end of the compound, amount of the W-7 Raney nickel catalyst is typically 3-5 moles per 1 mole of the compound.
The endpoint of the third or the reduction step of the process is typically determined by taking an aliquot of the product mixture and running thin layer chromatography and NMR thereon to determine presence of the desired product.
Extraction of the product is typically made with a solvent, such as ether, and purification is achieved by column chromatography. Purity of the product of about 99% is typically achieved.
The reduction step typically takes several hours to complete, such as 3-8 hours.
The novel and new products produced in this manner are the following diacetylenic keto acids and ketones:
COOHxe2x80x94(CH2)mxe2x80x94Cxe2x89xa1Cxe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)mxe2x80x94C(xe2x95x90O)xe2x80x94R and
Rxe2x80x94C(xe2x95x90O)xe2x80x94(CH2)mxe2x80x94Cxe2x89xa1Cxe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)mxe2x80x94C(xe2x95x90O)xe2x80x94R
where m is typically 2-8 carbon atoms and R is typically a cyclic or a multicyclic group containing 3-35 carbon atoms, more typically an aromatic monocyclic or a multicyclic group containing 6-15. The above compounds with the R group selected from phenyl, biphenyl and naphthyl groups have been found to be of special interest because of their fluorescence which makes them especially useful as optical markers.